The synthesis of the anti-cancer compound 2-methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)phenylamino]quinazolin-6-yl}-E-allyl)acetamide (CP-724,714) (1) on multikilogram
scale using several different synthetic routes is described.
Application of the Sonogashira, Suzuki, and Heck couplings to
this synthesis was investigated to identify a safe, environmentally
friendly, and robust process for the production of this drug
candidate. A convergent and selective synthesis of the candidate
was identified which utilizes a Heck coupling of a protected
allylamine to install the critical olefin.
Development of an efficient bond-forming sequence and optimization of reaction conditions are described for the synthesis of CP-945,598-01 (1 • HCl), a CB 1 antagonist in clinical studies for the treatment of obesity. Reordering of the bond-forming sequence provided a more efficient synthesis and avoided the use of phosphorous oxychloride. A telescoped reaction sequence (4 f 9) was developed to avoid a problematic isolation. Product isolations were developed so as to provide efficient throughput by minimizing solvent volumes and avoiding slow filtrations.
The synthesis of 6-ethoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid benzylamide (1) on multikilogram scale is described. The major challenge for the synthesis of this quinolone GABA partial agonist was in the isolation of product of acceptable purity for clinical studies due to the insolubility of this compound. Also described are efforts to circumvent a high-temperature cyclization required for the synthesis of the quinolone ring system.
A scalable route to 5-(2-carboxy-pyridin-2-yloxy)-benz[1,2,5]oxadiazole (3) is demonstrated. The synthesis was designed to
minimize potential safety issues with a previously practiced
route and, in particular, to avoid the handling of 5-hydroxybenzofurazan, which was found to decompose with a large
energy release at relatively low temperatures. The new route
builds the benzofurazan moiety onto a nicotinonitrile core to
avoid high-energy intermediates with low onset temperatures
of decomposition.
The process development is reported of a pivotal C–N bond formation involving ((7R,9aS)-octahydro-1H-pyrido[1,2-a]pyrazin-7-yl)methanol (2) undergoing nucleophilic aromatic substitution with 3-chlorobenzo[d]isoxazole (3) to furnish ((7R,9aS)-2-(benzo[d]isoxazol-3-yl)octahydro-1H-pyrido[1,2-a]pyrazin-7-yl)methanol (4) as a key intermediate for a family of compounds (1). Essential to the success of the coupling is the use of fluoride in combination with a phase transfer catalyst. The development of an alternative route to bicyclic piperazine 2 that uses l-aspartic acid (20) as a starting material to avoid the need for a classical salt resolution is described.
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